The hosts took the lead shortly after half-time, but Hojlund leveled on 62 minutes, six minutes after replacing Marcus Rashford, when the Danish striker tapped in Amad Diallo's deflected shot.
Two minutes from time, he beat Plzen goalkeeper Martin Jedlicka again with a clinical finish, turning around his marker after United captain Bruno Fernandes had found him inside the box with a clever free-kick.
Matej Vydra, a former Watford, West Brom, Reading, Derby and Burnley forward, opened the scoring for the hosts with a close-range finish three minutes after half-time.
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